Design of Potent Protein Kinase Inhibitors Using the Bisubstrate Approach

Article abstract of DOI:10.1021/jm00105a012

A new class of serine/threonine protein kinase inhibitors was designed by associating, in the same structure, mimics of both the ATP binding site and a protein substrate.Among the several potent antagonists which were obtained, the most active consists of isoquinoline-5-sulfonamide, as ATP mimic, and Ser-Arg₆, as peptidic moiety, bound by a -NH(CH2)2NH(CH2)2CO- linker.This compound, with a K_i of 0.1 μM toward protein kinase C (PKC) and 0.004 μM toward cyclic AMP dependent protein kinase (PKA), is respectively 60- and 750-fold more active than the commercial inhibitor H-7.